The 26S proteasome is a multi-subunit complex that effects targeted protein degradation in eukaryotic organisms. This proteasome is one of the highest value targets for drug discovery and development programs focused on cancer treatments. Efforts to develop anti-cancer drugs that target the proteasome are motivated by the success of bortezomib (VELCADE®), a frontline drug for the treatment of multiple myeloma and mantle cell lymphoma. Bortezomib is a peptide boronate that reversibly inhibits the proteasome via substrate imitation and labile bonding between its boronic acid moiety and active site threonine residues of the proteasome's proteolytic □ subunits. Bortezomib's substrate mimicry and its active site reactive warhead share structural features with most of the naturally occurring and designed proteasome inhibitors that have been reported to date, such as peptidyl aldehydes, peptidyl epoxyketones, and β-lactones. An analogue of a peptidyl epoxyketone natural product, carfilzomib (KYPROLIS®), has been approved for the treatment of multiple myeloma.
Although natural products in the β-lactone and peptidyl epoxyketone classes of proteasome inhibitors have been studied, those in the syringolin family have received much less attention. Syringolins were first isolated in 1998 from Pseudomonas syringae pv. syringae and display a twelve-membered macrocyclic lactam and an exocyclic dipeptide urea (See, FIG. 1). Irreversible proteasome inhibition by these molecules is due to the reaction of the α,β-unsaturated carbonyl moiety (i.e., the vinylogous amino acid) in their macrolactams with the catalytic threonine residues of the proteolytic subunits. Syringolin congeners mostly differ with respect to the dipeptide peptide urea moiety, but syringolins B and E are distinguished from the others by the absence of a unit of unsaturation in the macrolactam. The presence of the alkene likely strains the macrolactam such that it is more prone to form the inhibitory conjugate, as evidenced by the fact that syringolin A is the most potent congener. Syringolin derivatives have not been extensively studied in the context of anticancer drug development.
There is a need in the art to identify novel compounds that can be used to treat or prevent cancers, such as leukemia, in a subject. The present invention addresses and meets this need.